Scientists have been searching for treatments for neurodegenerative disorders like Alzheimer's and Parkinson's for many years, yet they remain elusive, even as increasing numbers of people are diagnosed with these devastating diseases. New research reported in Nature may help change that, however.
Cells have to deal with materials that have to be degraded or recycled, and they use an organelle called the lysosome to work as a kind of trash sorter that is crucial to cellular maintenance. The lysosome is known to be dysfunctional in many neurodegenerative disease states. When lysosomal dysfunction arises, trash can accumulate in cells and cause problems. This can be particularly harmful for neurons in the brain.
Research into a rare genetic disease in which the lysosome is dysfunctional revealed that the lysosome breaks down lipids or fats like cholesterol with the help of another special lipid molecule called bis(monoacylglycero)phosphate (BMP). In Batten disease, BMP levels are abnormally low, and lipids are not well transported within cells. Cholesterol buildup can cause inflammation and cell death.
"Lysosomes are basically the trash can of the cell," explained study co-author Jian Xiong, a postdoctoral scholar at Stanford University.
"Basically, BMP greases the machinery, allowing the lysosome to function at its best," added senior study author Monther Abu-Remaileh, an assistant professor at Stanford, among other appointments.
When the investigators found that BMP could degrade in the lysosome, they started looking for triggers. Work revealed that he culprit is an enzyme called PLA2G15.
In a cellular model of the neurodegenerative disease Niemann-Pick Disease type C, or NPC1, the scientists determined whether this degradation could be halted. With genetic engineering that stopped the expression of PLA2G15, there was a significant increase in BMP levels, and cholesterol stopped building up in the lysosome of the cells.
"This is literally the holy grail of this disease," said Abu-Remaileh. "It means you have a therapeutic handle that you can then test in animal models."
Mice that model NPC1 disease don't usually live for more than 70 days. But when expression of the PLA2G15 enzyme was halted in the mice, they lived almost 65% longer, and fewer of their neurons died. There were also improvements in neuroinflammation biomarkers and motor function.
Since the buildup of cholesterol in neurons with dysfunctional lysosomes is also seen in some neurodegenerative disorders, the researchers want to determine whether increasing BMP levels could work as a treatment option. Right now, tests are ongoing in cellular and animal models, and the researchers are looking for PLA2G15 enzyme inhibitors that cold work as drugs. Another therapeutic option that is being explored is the increase of BMP levels.
"We don't really have novel drug targets in neurodegeneration," said Abu-Remaileh. "These are bringing new hope."
Sources: Stanford University, Nature